Neurodegenerative disease affects over six million Americans and significantly burdens the U.S. health care system and economy. The pathogenic mechanisms underlying most of these devastating disorders are not well understood, even in disorders with an identified genetic cause, and unfortunately, there are no effective therapeutics for any of these diseases. The genetic cause of the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1; a dominantly inherited cerebellar ataxia causing cerebellar Purkinje neuron degeneration) is known, and studies to identify the underlying pathophysiology led me to uncover Nemo-like kinase (NLK) as a key protein contributing to pathogenesis. Disruption of the Nik gene in mice results in a pronounced cerebellar ataxia as well as other neurological abnormalities. Kinases are important to study because they are excellent pharmacologic targets, and NLK stands out as a potential drug target. The overarching hypothesis of my proposal is that understanding the mechanisms by which NLK contributes to SCA1 pathogenesis will lead to better understanding of other neurodegenerative diseases and will ultimately lead to the rational design of effective therapeutic interventions. During the mentored phase of the award, I will determine the role of NLK in SCA1 pathogenesis through genetic interaction studies in mice as well as biochemical approaches. These studies will be performed in Dr. Huda Zoghbi's laboratory at Baylor College of Medicine. Dr. Zoghbi has a history of outstanding contributions to science as well as a longstanding commitment to the mentorship of young scientists. As an independent investigator, I will determine the cause of the cerebellar ataxia phenotype in Nik mutant mice and study the role of NLK in nervous system development and function by generating and characterizing constitutive and conditional Nik knock-out mice. Furthermore, I will identify potential NLK targets and characterize their relevance to diverse neurodegenerative diseases. This strategy will provide me with a platform for further investigation of NLK function and its relevance to other neurodegenerative diseases. Information gained from these studies might lead to the development of effective therapeutics for a subset of neurodegenerative diseases.